No Increase in Intussusception With Rotavirus Vaccine

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This prospective, post-marketing study found no increased risk of intussusception following receipt of the pentavalent rotavirus vaccine in the U.S. among infants 4 to 34 weeks of age.

The risk was not higher in either the one-to-seven-day or the 30-day period following vaccination, compared with children receiving other vaccinations but not rotavirus, or compared with historical rates of intussusception.

The risk of intussusception was not elevated in U.S. infants who received the current pentavalent rotavirus vaccine (RV5), easing concerns raised by earlier studies, researchers found.

In the largest study of the issue to date, use of RV5 was not associated with a greater risk either one week or one month after administration, according to Irene Shui, ScD, of the Harvard School of Public Health in Boston, and colleagues.

The findings were consistent in analyses stratified by the number of doses the infants had received, the researchers reported in the Feb. 8 issue of the Journal of the American Medical Association.

"Although we cannot entirely exclude the possibility of a very low-level risk, the findings of our study strengthen the evidence base in favor of vaccination for effective control of severe childhood rotavirus disease," which has declined substantially in recent years, they wrote.

An earlier rotavirus vaccine -- the rhesus tetravalent rotavirus vaccine (Rotashield) -- was discontinued in 1999 because of an increased risk of intussusception.

Following prelicensure trials that did not demonstrate a greater risk of the intestinal disorder, there have since been two new rotavirus vaccines introduced -- RV5 (RotaTeq) in 2006 and a monovalent vaccine (RV1, Rotarix) in 2008.

Although a postlicensure study using two years of data from the Vaccine Safety Datalink in the U.S. did not show an increased risk of intussusception with RV5, postlicensure data from Australia, Mexico, and Brazil suggested the possibility of a low level of risk with the two newer vaccines, mostly in the first week after the first dose in the series.

The current study reexamined the issue using an additional two years of data from the Vaccine Safety Datalink -- a collaboration between the CDC and managed care organizations. The analysis included information on RV5 doses administered to infants ages 4 to 34 weeks from May 2006 to February 2010. RV1 was excluded because it was infrequently used.

During the study period, clinicians administered 786,725 RV5 doses, including 309,844 first doses. There were 56 cases of intussusception identified through electronic medical records -- 30 in infants who received RV5, and 26 in those who received other recommended vaccines but not RV5.

After adjusting for age, there was no increased risk of intussusception in either the first week after administration of the vaccine (RR 0.95, 95% CI 0.37 to 2.63) or in the first 30 days (RR 0.90, 95% CI 0.10 to 11.08) in an analysis of all doses combined. The findings were similar when stratified by dose.

A look at historical trends in intussusception rates did not show any change after introduction of RV5, which is consistent with a study published last month. Introduction of RV5 has been associated with a marked decrease in cases of severe rotavirus disease, however.

For the first week after administration of the vaccine (all doses combined), there were 21 cases of intussusception during 2006 to 2010, which is comparable to the 20.9 cases expected based on data from 2001 to 2005 (standardized incidence ratio [SIR] 1.01, 95% CI 0.62 to 1.54).

For the first month after administration, there were four cases during the study period, which compares with 4.3 expected cases (SIR 0.92, 95% CI 0.25 to 2.36).

The SIRs in the analyses of first doses only were 1.23 (95% CI 0.50 to 2.54) for the first month and 1.21 (95% CI 0.03 to 6.75) for the first week. Taking the upper limit of the confidence interval (6.75) would equate to one intussusception case in the first week per 65,287 first doses of RV5.

It is unclear why the U.S. studies have not found a greater risk of intussusception with the rotavirus vaccines and some of the international studies have, according to the researchers.

"Because intussusception is a rare event, we cannot rule out a chance finding of risk in Australia and Mexico as well as the possibility of not detecting a low-level risk in the United States and Brazil," they wrote, noting that there could also be environmental or genetic factors that differ between the populations, thus modifying the association.

The authors acknowledged some limitations of the study, including the inability to review medical records for the historical intussusception cases, possible confounding caused by differences between infants who received RV5 and those who did not, and low statistical power to detect low-level risks in some of the analyses stratified by dose.

The study was supported in part by the Vaccine Safety Datalink contract with America's Health Insurance Plans (AHIP), funded by the CDC.

Shui reported receiving institutional support from AHIP for writing or reviewing a manuscript and for travel. Her co-authors reported relationships with AHIP, the CDC, MedImmune, Kaiser Colorado Institute for Health Research, the Vaccine Safety Datalink, Merck, GlaxoSmithKline, Pfizer, Sanofi Pasteur, and Novartis.

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